A Mysterious Brain Region Contributes to Aberrant Cognitive Processing in People with Migraine

By Neil Andrews | June 18, 2024 | Posted in

A brain imaging study reveals increased activity in a pain circuit, extending from the claustrum to a specific area of the cortex, when those living with migraine perform a cognitive task but are not in pain.

A long-neglected area of the brain called the claustrum – once proposed by a Nobel Prize-winning scientist to be the seat of consciousness – plays an important role in the cognitive function of those living with migraine. That is according to a new brain imaging study from a collaboration amongst researchers in the US and Canada.

The investigators, led by David Seminowicz, University of Western Ontario, London, Ontario, Canada, and Brian Mathur, University of Maryland, Baltimore, US, used functional magnetic resonance imaging (fMRI) to show that, while the claustrum responded to experimental pain in healthy subjects, it also showed excessive activity when individuals with migraine were asked to complete a cognitive task, even though they weren’t experiencing pain at the time they completed the task.

The team, including first author Brent Stewart, further demonstrated the existence of a neural pathway projecting from the claustrum, a subcortical gray matter structure, to the posterior inferior dorsolateral prefrontal cortex (piDLPFC). The latter is a specific region of the cortex that also showed an elevated response during the pain-free cognitive task in migraine patients.

In addition to showing that pain alone can activate the claustrum-piDLPFC circuit, and elucidating a potential mechanism underlying cognitive deficits in people with migraine even when they were not experiencing pain, the work suggests the claustrum could one day be a therapeutic target to correct those deficits.

“I think this paper is excellent. It’s really interesting and raises a number of thought-provoking questions,” according to Anna Taylor, a pain researcher at the University of Alberta, Canada, whose own paper on the contribution of the claustrum to acute and chronic pain in mice appeared in the same May 6, 2024, issue of Current Biology as the current study. (Also see a related commentary on both studies.)

“They show a recruitment of a cognitive-associated region that is different in those with migraine compared to healthy controls, particularly the posterior inferior dorsolateral prefrontal cortex,” Taylor further said. “This is a region they show is active in response to an acute pain stimulus in healthy controls, but also when migraine patients are thinking about something hard, even though they had no pain during the cognitive task,” according to Taylor.

“Maybe to be a little poetic or philosophical: It’s like there’s an echo of pain that gets woven into the fabric of the cognitive processes of those with migraine, so that there is activation of these pain-associated processes, even though they’re not in pain currently and are not thinking about pain,” Taylor continued.

Jump-starting a field
It took time for research on the claustrum to take off, the authors told Migraine Science Collaborative, because of the shape and position of this structure in the brain.

“The claustrum has a long history of being the most enigmatic nucleus in the brain,” said Mathur. “That is because it’s hidden in the middle of the telencephalon [the cerebrum] and has a very odd shape: It’s shaped like a sheet instead of like a ball. And this has made it very difficult to figure out what it does in relation to cognition or action.”

But a new theory proposed in 2005 by the Nobelist and co-discoverer of the helical structure of DNA would eventually stimulate interest in the shadowy structure.

“The claustrum has an interesting backstory to it. Because it’s been so hard to study because of its shape, it’s given rise to many wild theories of its function. And one of the most famous of those theories is from Francis Crick, who suggested it was involved in consciousness because it’s connected to all the different parts of the cortex,” according to Mathur.

“I think [Crick’s theory] had a big impact in inspiring a generation of researchers who were captured by the magic and the elusiveness of the claustrum,” said Taylor.

Along with that heightened interest, the development of new experimental tools to study the claustrum allowed researchers like Mathur to better understand its function.

“We’ve discovered that it’s important for something that we call cognitive control, which is a sort of umbrella ability to muster cognitive resources to meet task demands. And so, anytime that you perform any sort of cognitive function, a certain collection of brain regions turns on – that’s what we call a cognitive network. And we found that the claustrum seems to be rather important for supporting the co-activation of these regions to give rise to these networks that support cognitive control,” Mathur said of the import of his previous research.

A new hypothesis
Over the years, Mathur would begin to collaborate with Seminowicz, his co-senior author, on a number of studies to bring Mathur’s claustrum research in animals into humans, and then to back-translate that work into additional animal studies. The current study collaboration made sense considering Seminowicz’s own research examining the cognitive dimensions of pain and the potential to target them therapeutically.

What the investigators knew about the claustrum, and about pain, would lead to a new hypothesis tested in the current study.

“A prediction of the hypothesis that the claustrum supports cognitive networks was that anything that activates a cognitive network should activate the claustrum. And it turns out that pain activates cognitive networks. So our hypothesis was that pain should activate the claustrum,” Mathur said.

To test the idea, the researchers made use of data that Seminowicz had previously generated from a clinical trial of a mindfulness intervention for migraine treatment.

In initial experiments, the investigators applied a painful heat stimulus to the forearm in healthy study participants, which increased activity in the claustrum, according to fMRI scans.

But, to reveal a role for the claustrum per se, it was important to show that this activity emanated specifically from the claustrum and not from the insula, a nearby cortical area that the claustrum nestles up against and that has long been recognized for its own contribution to pain processing. The imaging results would confirm that the signal coming from the claustrum differed from that coming from the insula, which Taylor said was one of the strengths of the study.

“The claustrum kind of gets lumped into insular activity and has long been ignored. This study does a really good job parsing the claustrum signal from the insula signal,” she said.

Interestingly, the fMRI signal increased in the claustrum even in mere anticipation of pain. Here, the investigators looked to a second dataset of healthy participants who underwent scanning while receiving a painful thermal stimulus to the leg. Before receiving the stimulus, participants heard a doorbell sound, which set up an anticipation that the sound would be followed by pain.

Results indicated significant activation in the claustrum in response to this pain-predictive auditory cue. That finding further built the case for the claustrum’s involvement in pain.

What happens during migraine?
The research team next compared healthy participants to those with migraine. The first question was whether the two groups differed in brain responses to a pain-free cognitive task of varying difficulty, considering previous evidence of altered brain activity during cognitive task performance in different chronic pain conditions, including migraine. Here, the investigators presented participants with three numbers, two of which were the same, and the participants then had to press, among three buttons on a response pad, only the one button that corresponded to the unique number.

Both the migraine and healthy control groups showed increased activity in some brain regions and decreased activity in others during performance of the task. However, those with migraine showed a more widespread activation throughout the brain compared to the control group. Further analysis revealed that a variety of different subsets of brain regions all showed greater activity in the migraine group.

What might underlie these differences? Additional experiments indicated that the piDLPFC – a part of the prefrontal cortex, which is responsible for higher-order cognitive functions – also showed higher activity only in the patients, when they performed the pain-free cognitive task of the highest difficulty. Further, while this brain region showed increased activity in response to painful thermal stimulation in both groups, the activity was greater in the migraine group.

“There’s a large cluster of the brain showing activity in the migraine patients when they’re performing the cognitive task that was absent in the results of the healthy controls – it’s this extra region, the piDLPFC, that’s activated,” first author Stewart told MSC.

Considering the role of the claustrum in cognitive processing, the next question was whether altered activity in the claustrum could explain the findings. That is, the team wanted to see if there was a link between altered cognitive activity in the patients and altered claustrum activity. That’s exactly what the results indicated – namely, increased claustrum activity at the beginning of the cognitive task with the highest difficulty, and also at the onset of thermal pain in other experiments, in the migraine group, compared to controls.

The claustrum also showed more spontaneous activity at rest in those with migraine. And, only the patients showed decreases in coordinated activity between the piDLPFC and other brain regions.

From the claustrum … to where?
The experiments had revealed a role for changes in the claustrum, and in the piDLPFC, in migraine patients undertaking a cognitive task. Was there a link between the activity in these two brain regions? That was in fact the case, with both regions becoming co-activated at the onset of the difficult cognitive task and at the onset of thermal pain.

Thus far, the imaging results had revealed what’s known as functional connectivity, or the coordinated activity of different brain regions. But the researchers were also interested in anatomical connections between different brain regions, known as structural connectivity. So they used a different type of brain imaging that allows for assessment of that feature.

As predicted, structural connectivity was present between the claustrum and piDLPFC, here in a different sample of healthy participants from a research effort called the Human Connectome Project.

Finally, the investigators wanted to understand the direction of communication between the claustrum and piDLPFC – what’s known as effective connectivity. Put another way: Did the signal go from the claustrum to the piDLPFC, or the reverse? A statistical approach called causal modeling answered that question, providing evidence consistent with the idea of increased signaling from the claustrum to the piDLPFC, at the onset of the difficult cognitive task, in the migraine group.

Claustrum and migraine

Credit: Stewart et al. Curr Biol. 2024 May 6;34(9):1953-1966.e6.

What does it all mean?
One question the study could not address is what the alterations in cognitive processing actually reflect in those with migraine.

“Is the activity of this extra region [the piDLPFC] somehow a compensatory mechanism helping a migraine patient think? Is it a diversion of resources that is a source of some of these cognitive difficulties? Does it represent that there’s a qualitatively different process that the brain is following in terms of decision making? Is it factoring in possible pain or past pain into current decisions?” Stewart mused on the various possibilities.

One open question that Taylor pointed to is whether the claustrum could be targeted for therapeutic purposes.

“There are specific markers for different claustrum neurons, so you could feasibly target or design a drug that would target claustrum neurons more or less specifically. But that’s in the realm of imagination at this point. But there are other ways or interventions that can impact cortical function broadly, that likely tie in the claustrum. As examples, mindfulness-based meditation, and psychedelics, all reorient the cognitive-associated regions, which may be helpful in treating symptoms associated with migraine,” according to Taylor.

But there is a much bigger picture to keep in mind, considering how widespread the claustrum’s tentacles are throughout the brain.

“The idea that the claustrum projects to almost the entire cortex – it’s really hard to undersell that,” Taylor said. For instance, she noted evidence of a role for cortical projections from the claustrum in regulating sleep. This is of relevance to migraine, considering the sleep disturbances that people with migraine, and chronic pain more generally, often experience.

As for additional studies, the investigators said they are now looking into whether the findings will hold up when subjects complete different cognitive tasks, to learn if the claustrum-piDLPFC circuit plays a role in other aspects of cognition, too.

Finally, when asked about the take-home messages the researchers would like readers to get from their paper, Mathur pointed not only to the main finding but also to how it was generated.

“To put it very succinctly: We have discovered a novel pain pathway likely involved in the cognitive aspects of pain. This requires empirical data moving forward to illuminate what exactly it’s doing,” Mathur said. “But I would add that the way we did this study, I think, is really cool. We looked not only at functional connectivity and effective connectivity, but also at structural connectivity as well. That’s not done very often, and it really speaks to the strength of the data. I’m really proud of the rigor that we put into this study.”

Neil Andrews is a science journalist and executive editor of the Migraine Science Collaborative. Follow him on X (formerly Twitter) @NeilAndrews

Pathological claustrum activity drives aberrant cognitive network processing in human chronic pain.
Stewart et al.
Curr Biol. 2024 May 6;34(9):1953-1966.e6.

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Neil Andrews is a science journalist and editor based in New York City. He has over two decades of experience covering science and medicine for expert and non-expert audiences alike. He is also the executive editor of the Migraine Science Collaborative, where he manages the day to day operations of the site. Previously he was the executive editor of the Pain Research Forum.

When not thinking and writing about neuroscience, Neil spends much of his free time on his Peloton and exploring NYC. He is also on a quest to satisfy his coffee cravings by visiting every independent coffee shop in the city. Follow him on Twitter @NeilAndrews.



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